It is known that SGLT1 (i.e., Sodium-Glucose Co-transporter 1) contributes to a great portion of absorption of glucose and galactose in the small intestine. It is reported that human SGLT1-deficiency in patients causes glucose-galactose malabsorption. Furthermore, it is confirmed that the expression of SGLT1 in the small intestine increases in diabetic patients and it is thought that increased sugar absorption in diabetic patients is caused by the high expression of SGLT1 in the small intestine.
From these knowledge, a SGLT1 inhibitor is expected to normalize the blood glucose level, since it blocks glucose absorption in the small intestine. Therefore, a SGLT1 inhibitor is considered to be effective against diabetes and diabetic complications associated with hyperglycemia, specifically retinopathy, nephropathy and neuropathy which are known as microangiopathy, and cerebrovascular disease, ischemic heart disease and membrum-inferius arteriosclerosis obliterans which are known as macroangiopathy. Moreover, it is thought to be effective against obesity by inhibiting the inflow of glucose into the body (non-patent literatures 1 and 2).
In addition, SGLT1 is expressed in cardiac muscle cells. It is known that GLUT1 and GLUT4 (Glucose Transporter Type 4) usually have a role in uptake of glucose to cardiac muscle cells and the contribution of SGLT1 is small. However, the expression of SGLT1 is induced in the cardiac muscles of mice into which was introduced mutated genes of PRKAG2 (gamma 2 subunit of AMPK (AMP-Activated Protein Kinase)) which is a responsible gene of familial hypertrophic cardiomyopathy (glycogen accumulation-type myocardosis), or mice which underwent myocardial ischemia treatment, and SGLT1 is reported to have contributed to the uptake of glucose to cardiac muscle cells in these pathologies. Glucose incorporated by SGLT1 is thought to be excessively accumulated or metabolized within cardiac muscle cells and impair the cells. It is reported in the former mouse model that accumulation of glycogen in the cardiac muscle is actually inhibited by the treatment of phlorizin which is a non-selective SGLT inhibitor.
From these knowledge, a SGLT1 inhibitor is thought to be effective against hypertrophic cardiomyopathy and ischemic heart disease by inhibiting uptake of excess glucose into cardiac muscle cells (non-patent literatures 3 and 4).
SGLT1 is stabilized by epidermal growth factor receptors (i.e., surface proteins on many kinds of cancer cells) in cancer cells. It is known that transporters of glucose, lactic acid, and amino acid, etc. are involved in nutrition supply to cancer cells, and especially, regarding the transportation of glucose, SGLT1 and GLUT1 supply glucose to cancer cells, continuously. When glucose is not supplied over a long period of time, cells are destroyed by autophagy.
From these knowledge, a SGLT1 inhibitor is thought to inhibit supply of glucose to cancer cells and show anticancer activity (non-patent literatures 5 and 6).
Since carbohydrate in diet is degraded to monosaccharide in the gastrointestinal tracts and is absorbed in the upper gastrointestinal tracts, not so many sugar would reach the lower gastrointestinal tracts. However, when drugs which delay and/or inhibit glucose absorption are administered, or a large amount of resistant polysaccharide are ingested, undigested sugar would be retained in the lower gastrointestinal tracts and the undigested sugar retained in the lower gastrointestinal tracts would cause osmotic diarrhea.
The amount of monosaccharide in the lower gastrointestinal tracts is increased by the inhibition of glucose absorption by a SGLT1 inhibitor. Therefore, it is believed that a SGLT1 inhibitor is effective against constipation.